Breast cancer is the most commonly diagnosed cancer in women worldwide. Targeted therapies for treating breast cancer have helped to reduce the death rate from the disease, according to results from clinical trials. These treatments inactivate specific molecules in cancer cells that are necessary for cell growth and survival, unlike more general treatments, such as chemotherapy, that interfere with all cells that may be dividing. Because targeted therapies are more precise, they generally have fewer side effects. However, they also may have limited effectiveness in some patients whose tumor growth depends on molecules that are not exclusively targeted by the agents or whose cancer mutates to use other growth pathways.

How is HER2-positive breast cancer different from other types?

HER2-positive (HER2+) breast cancers are defined as those that have an excess number of HER2 genes or over-produce the protein product of the HER2 gene, the HER2 cell surface receptor. HER2 is a member of the epidermal growth factor receptor (ErbB) family of genes, which encode proteins that are cell surface-bound tyrosine kinase proteins. Mutation or over-production of these molecules stimulates cell division and uncontrolled growth. Fifteen percent to 20 percent of breast cancers are HER2+. These tumors tend to grow faster and are generally more likely to recur than tumors that do not overproduce HER2.

What was the ALTTO trial?

ALTTO was a clinical trial designed to compare treatments for early stage HER2+ breast cancer in women who had also received chemotherapy. From June 2007 to July 2011, more than 8,000 women from 946 participating sites in 44 countries were randomly assigned to receive trastuzumab alone, lapatinib alone, or a combination of lapatinib and trastuzumab. Specifically, ALTTO was designed to determine which treatment was more effective, which was safer for patients, and whether additional benefit could be derived by taking the drugs together, either in tandem or at the same time. The ALTTO clinical trial was unique in that, for all of patients, there was central pathology review of the primary tumor, including re-evaluation of the cancer's estrogen receptor (ER), progesterone receptor (PR), and HER2 status, before patients were randomly assigned to one of the trial's four treatment groups. About 15 percent to 20 percent of breast cancers are HER2-positive and about half of the HER-2 positive cancers also express ER and/or PR.

How do the HER2-positive cancer drugs lapatinib and trastuzumab work?

Trastuzumab (Herceptin), a drug developed in 1990s to target HER2+ breast cancers, is a large monoclonal antibody that, once injected into patients, binds to the portion of the HER2 protein that sits on the outer surface of the cancer cell. It was approved for use in the United States in 1998 and in Europe in 2000 to treat metastatic HER2+ breast cancer in combination with chemotherapy. In 2006, European and U.S. regulators approved the use of trastuzumab, with chemotherapy, to treat early stage HER2+ breast cancer. Trastuzamab is given intravenously (into a vein).

Lapatinib (Tykerb) was approved in 2007 for use in combination with capecitabine, a chemotherapy drug, for the treatment of advanced or metastatic HER2+ breast cancer in patients who have received prior treatment, including an anthracycline drug, a taxane drug, and trastuzumab. Lapatinib acts by entering a cancer cell and binding to the part of the HER2 protein that lies just beneath the cell's outer membrane. Lapatinib is given orally (a pill by mouth).

Is trastuzumab always effective in HER2+ women?

Although trastuzumab is effective against HER2+ breast cancer in many patients, some patients do not respond and others will acquire resistance to it. Edith Perez, M.D., an oncologist at the Mayo Clinic in Jacksonville, Florida, led a North Central Cancer Treatment Group (NCCTG) trial that showed a 52 percent reduction in cancer recurrence among women with early stage HER2+ breast cancer who received trastuzumab. Martine Piccart, M.D., Ph.D., professor of oncology at the Universite Libre de Bruxelles, Belgium, led the HERA (HERceptin Adjuvant) trial, a Breast International Group (BIG) trial that showed very similar results.

How is lapatinib different from other drugs used to treat breast cancer?

Lapatinib is a second generation drug that is designed to strike multiple targets. It is a tyrosine kinase inhibitor that enters a cancer cell and binds to the part of the HER2 protein that sits just beneath the cell's outer membrane. Its effect on the function of other proteins in the ErbB family of proteins that may also fuel cancer cell growth is being studied. As a small molecule, it may also be able to cross the blood-brain barrier to treat the spread of breast cancer to the brain and central nervous system that trastuzumab cannot reach.

What studies have been done to prove the effectiveness of lapatinib?

To date, over 200 clinical trials of lapatinib have been conducted. Specifically, the FDA's approval was based on a phase III trial involving 399 patients that showed lapatinib plus capecitabine provided a 28 percent to 43 percent reduction in the risk of disease progression in women with advanced or metastatic HER2+ breast cancer compared with chemotherapy alone.

In addition, some studies suggested that lapatinib could offer clinical benefit in HER2+ breast cancers that do not respond to trastuzumab. Researchers did not know how lapatinib treatment would compare with trastuzumab treatment.

What are some of the potential side effects of lapatinib and trastuzumab?

Both drugs have been associated with a number of side-effects. Note that the list below may not be inclusive:

Lapatinib has been associated with gastrointestinal side effects, including diarrhea, nausea, and vomiting; skin disorders, including rashes and hand-foot syndrome; pain in the back and the extremities; and breathing difficulties. In earlier clinical trials, diarrhea was the most common side effect, resulting in discontinuation of the medication.

Trastuzumab has been associated with heart-related side effects, in particular decreases in left ventricular ejection fraction (LVEF), or the volume of blood that is pumped out of the left ventricle (the main pumping chamber of the heart) with each contraction. However, this side effect is rare and reversible following the completion of treatment. Other side effects associated with trastuzumab include nausea, vomiting, diarrhea, headaches, pain, fever and other flu-like symptoms, and rashes.

Patients who receive trastuzumab along with chemotherapy may experience side effects that are different from those of patients who take trastuzumab by itself. For example, anemia (a condition in which the number of red blood cells is below normal) and infection, primarily mild upper respiratory infection, have been seen more often in patients given trastuzumab with chemotherapy compared with those receiving trastuzumab alone.

How was the ALTTO trial modified in 2011?

On September 9, 2011, the leadership of ALTTO announced that it would discontinue Arm 2 of the trial (the lapatinib alone arm). A review of efficacy data by the Independent Data Monitoring Committee was triggered after a pre-specified number of events in the trial was reached, as outlined in the study's protocol. An analysis of these events showed a statistical imbalance in breast cancer recurrence between Arm 1 (the trastuzumab alone arm) and Arm 2. According to Edith A. Perez, M.D., ALTTO's principal investigator in the United States, "participants assigned to the lapatinib alone arm are not likely to do as well as participants assigned to trastuzumab alone." For more information on this trial modification, go to the ALTTO trial website at http://alttotrials.com/patients.php .

What were the results of the ALTTO trial as reported in June 2014 at the ASCO annual meeting?

The purpose of the ALLTO trial was to identify the best of four different methods of delivering HER2-targeted therapy to patients with early stage HER2+ breast cancer. However, results from the three trial arms that remained open after the 2011 protocol modification did not show additional benefit for combination therapy (lapatinib plus trastuzumab or lapatinib followed by trastuzumab) compared with trastuzumab treatment alone. This finding was unexpected, particularly in light of results from the NeoALLTO trial, a sister trial to ALTTO, that showed combination treatment with lapatinib and trastuzumab yielded better results than single-agent therapy alone.

Although the results of ALTTO did not show additional benefit for combination therapy with lapatinib and trastuzumab, researchers still gained valuable information about the benefits and harms of these drugs. Moreover, because of the large international collaboration that supported ALTTO, the results of this trial were available sooner than they would have been otherwise. Indeed, lessons learned from ALTTO helped scientists launch a phase III clinical trial called OlympiA (Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer) more quickly. For more information about OlympiA, please go to http://clinicaltrials.gov/show/NCT02032823.

How were tissue samples examined and stored in the ALTTO trial?

For ALTTO patients in North America, paraffin samples of their tumors were tested and stored at the Mayo Clinic in Rochester, Minnesota. The European Institute of Oncology in Milan, Italy, tested and stored paraffin samples for Europe and the rest of the world. These tissue samples can be used in future translational research studies.

Besides HER2, what other molecules did the ALTTO investigators focus on in the tumor samples?

The researchers also examined the PTEN tumor suppressor gene (because cancers that have lost this gene are thought to respond best to lapatinib). They also collected information on p95 HER2, which is a truncated form of HER2 that does not bind trastuzumab. Cancer cells that have elevated amounts of p95 HER2 may be resistant to trastuzumab, but they may be sensitive to other HER2-target agents, such as lapatinib.

What other biological samples did ALTTO investigators collect? Blood samples were collected from all patients to look for molecular markers that may predict clinical outcome, and, in a subset of about 2,000 patients, additional blood and frozen tumor samples were gathered for future research on circulating tumor cells and proteomics analyses (studies of proteins and their interactions). These biological materials are stored in Rochester, Minnesotta, and in Brussels, Belgium.

How was ALTTO funded?

Funding for ALTTO was provided by the National Cancer Institute (NCI), part of the National Institutes of Health, and GlaxoSmithKline (GSK), the pharmaceutical company that developed lapatinib. NCI contributed to each U.S. participating site a standard $2,000 per patient cost (standard at the time the trial opened for enrollment) for the ten-year study, as well as the basic infrastructure for running all trials via existing grants. GSK's contribution is considered proprietary information.

What new FDA-approved drugs are available to treat HER2+ breast cancer?

Two new drugs have been recently approved by the FDA for treating HER2+ breast cancer:

Ado-trastuzumab emtansine, or T-DM1 (Kadcyla), was approved in February 2013 for the treatment of women with HER2+ metastatic breast cancer who have received prior treatment with trastuzumab and taxane chemotherapy.